Project Summary Atherosclerosis causes heart attack and stroke and accounts for nearly 30% of deaths in the United States. Atherosclerosis is caused by subendothelial retention of low-density lipoproteins, which leads to a macro- phage-driven inflammatory response. Existing therapies for atherosclerotic cardiovascular disease (ASCVD) focus on lowering serum lipid levels and have been efficacious in reducing disease burden, but substantial re- sidual risk or cardiovascular events in treated individuals remains. Targeting inflammation in atherosclerosis may further reduce ASCVD mortality, although broadly anti-inflammatory therapies may incur a risk of immuno- suppression. The long-term objective of this research is the elucidation of mediators and pathways that may form the basis for targeted anti-inflammatory therapies in atherosclerosis, focusing on the nuclear receptor Liver X Receptor (LXR). Activation of LXR by oxidized cholesterol or pharmacological agonists promotes cho- lesterol efflux to high-density lipoproteins and suppresses inflammation. LXR agonists suppress atherogenesis in mouse models, an effect that has been linked to the anti-inflammatory function of LXR. LXR has been pro- posed to regulate inflammation through either a direct repressive function at inflammatory genes or stimulation of cholesterol efflux, but the mechanism and role of inflammation suppression by LXR in atherosclerosis has not been definitively established. Preliminary studies described here have established the genome-wide speci- ficity and genetic requirements for inflammatory gene repression by LXR in highly specific experimental sys- tems that avoid off-target effects of the LXR agonist used in past mechanistic studies of this effect. The pro- posed research is aimed at defining the molecular determinants and anti-atherogenic effects of inflammatory gene repression by LXR in macrophages. In Aim 1, genome-wide enhancer profiling studies will be used to establish the genomic elements and transcription factor binding sites involved in LXR?s anti-inflammatory ef- fect. Aim 2 will utilize mouse models of atherosclerosis, genetic manipulation of these models, and tran- scriptomic assays to clarify the potential for inflammation suppression by LXR in atherosclerotic lesions and the role of macrophage LXR in anti-atherogenic effects of LXR agonists. This research will reconcile conflicting mechanistic hypotheses about LXR?s anti-inflammatory function and support the development of selective or targeted LXR agonists that may allow clinical translation of LXR?s anti-atherogenic activity.